The targeted mass spectral analysis of complex mixtures has conventionally been carried out using a triple quadrupole mass spectrometer. In these instruments, the mass-to-charge ratio range of precursor ions is selected by a first quadrupole mass analyzer. The precursor ions are fragmented in a gas-filled collision cell and then a particular fragment is selected by a second quadrupole mass analyzer. This allows filtering out only precursor and corresponding fragment ions of interest. It thereby provides a robust quantitative method for targeted analysis, where the targets are known but may be present in very low levels compared with other analytes.
Due to their nature of operation, quadrupole analyzers allow only ions in a narrow window of mass-to-charge (m/z) ratios to be transmitted. Though this m/z ratio window is transmitted with an efficiency that is sometimes greater than 50% and detected using a Secondary Electron Multiplier (SEM) with single ion sensitivity, ions of all other m/z are lost on the analyzer rods. This wasteful operation hinders fast quantitation analysis, where multiple target compounds are desirably analysed within a limited time. Quadrupole mass analyzers must jump from one m/z to another, with their effective duty cycles being quite low (0.1% to 10%, depending on the number of targets).
Further difficulties exist in relation to accurate quantitation in elemental analysis of analytes in quadrupole-based Inductively Coupled Plasma Mass Spectrometry (ICP-MS), due to molecular interferences.
Alternatives to triple quadrupole mass spectrometers are known. For example, simultaneous acquisition of all fragments from all precursors can be performed to provide a single high-resolution, high mass-accuracy spectrum. A subsequent search for ions of the targeted m/z ratio can then be performed. Analyzers using orbital trapping technology (for example, the mass analyzer marketed as Orbitrap™ manufactured by Thermo Fisher Scientific), Fourier Transform Ion Cyclotron Resonance (FT-ICR) analyzers and those based on Time-of-Flight (TOF) are considered examples of accurate mass analyzers for this application.
However, such accurate mass analyzers have significant limitations for modern targeted analysis experiments. For example, the detection limits and dynamic range for orthogonal-acceleration TOF analyzers are significantly worse than in triple quadrupole spectrometers, due to low transmission and limitations of the detection electronics. Meanwhile, orbital trapping-based analyzers (as well as any other analyzer utilising image current detection, such as FT-ICR or electrostatic traps) have: a sensitivity that is limited by image current detection; a dynamic range limited by charge capacity; and a speed or duty cycle limited by the necessity to detect each transient for tens to hundreds of milliseconds. As a compromise, a combination of an accurate mass analyzer with a quadrupole mass filter allows the combined advantages of all-fragment detection with those of reduced dynamic range resulting from narrow m/z isolation.
For both high-resolution approaches, the desire to minimize the Coefficient of Variation (CV) of mass peak intensity limits the number of measurement points across narrow (0.5-2 sec wide) peaks possible in modern Gas Chromatography (GC) or Ultra-High Performance Liquid Chromatography (UHPLC). Examples of existing such systems are discussed in “New Trends in Fast Liquid Chromatography for Food an Environmental Analysis”, Núñez et al (Journal of Chromatography A, 1228 (2012) p. 298-323). Overcoming these difficulties remains a challenge in this area.